Abstract

Abstract 2838

Background:

Ruxolitinib (rux), a potent oral JAK1 & 2 inhibitor, has demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life in 2 phase 3 COMFORT studies in MF patients (pts). Consistent with rux's known mechanism of action, anemia was one of the most frequently reported adverse events (AEs) and was generally transient and manageable leading to discontinuation in only 1 pt. In clinical practice, anemia can be managed with ESAs, which promote red blood cell proliferation via cytokine receptors that signal through the JAK pathway. Because these agents act upstream of rux in the JAK2 pathway, it is important to determine the effects of these medications on the safety and efficacy of rux. This post hoc analysis evaluated the safety and efficacy of rux in pts receiving concomitant ESA in COMFORT-II.

Methods:

COMFORT-II is an open-label, randomized, multicenter study. Pts were randomized (2:1) to receive rux 15 or 20 mg bid or best available therapy (BAT; as selected by the investigator). Use of ESAs (eg, darbepoetin alfa, epoetin alfa, epoetin nos), although not prohibited, was discouraged for pts randomized to rux because ESAs can increase spleen size, which could confound efficacy analyses. Spleen volume was assessed by MRI or CT every 12 wk. The rate of transfusions was calculated as the number of units transfused per exposure duration (typically 12 wk).

Results:

Concomitant use of ESA was reported for 13 (PMF, n = 10; PET-MF, n = 2; PPV-MF, n = 1) of the 146 pts who were treated with rux (darbepoetin alfa, 2% [n = 3]; epoetin alfa, 6% [n = 9]; epoetin nos, < 1% [n = 1]). The median exposure to rux was similar for pts who received an ESA (+ESA group; 500 d) vs those who did not receive ESA (468 d), and the median dose intensity of rux was the same for each group (30 mg/d). As shown in the table, 8 pts (62%) had no change, 2 pts (15%) had a decrease, and 3 pts (23%) had an increase in the rate of packed red blood cell (PRBC) transfusions per mo after the first administration of ESA compared with 12 wk before ESA use. Six wk prior to the first administration of ESA, 10/13 pts (77%) had grade 3/4 hemoglobin abnormalities; however, 6 wk after the administration of ESA, most pts' conditions improved to grade 2 (7/13 [54%]). The majority of pts (77%) did not have any change in their reticulocyte counts within the 6 wk before and after the administration of ESA; 1 pt (8%) had a marked increase; for 2 pts (15%), the data were not available. The AEs reported in pts who received ESA were similar to those previously reported with rux. Serious AEs were reported for 8 pts in the +ESA group (3 events in 2 pts that were possibly related to study drug). Within the last assessment prior to and the first assessment after the first administration of ESA, 7/9 evaluable pts (78%) had spleen volume reductions.

Conclusions:

In this analysis, although the sample size is small, rux was generally well tolerated in pts who received ESA, and the tolerability profile of rux was similar to that reported in previous studies. Rux-treated pts who received ESA generally did not have any change in their transfusion rates, but the rate of grade 3/4 hemoglobin abnormalities decreased within 6 wk of the first administration of ESA, suggesting that the use of ESA in combination with rux was beneficial in some pts. ESA did not appear to affect the efficacy of rux concerning spleen size reduction. The use of ESA for the treatment of anemia is common in clinical practice, and further analyses in combination with rux in this pt population are warranted.

Table.
PtTransfusion Ratea (units PRBC/month)Hemoglobin Valueb (g/L)Reticulocyte Countb (× 109/L)Change in Spleen Volume From Baselinec (%)
Before ESAAfter ESABefore ESAAfter ESABefore ESAAfter ESABefore ESAAfter ESA
2.9 2.9 62 74 42.5 41 −13 −20 
2.2 10.7 75 60 110 114 −22 NA 
1.8 0.7 62 NA 90 NA −29 NA 
0.7 68 66 61 73 −8 −15 
2.9 74 74 167 200 +11 −3 
0.7 2.2 67 73 74 NA −3 NA 
78 88 39 260 −36 −50 
81 80 82 73 −45 −34 
76 80 42 43 −65 −67 
10 74 91 49 76 −54 −58 
11 76 82 106 126 NAd −6 
12 87 84 247 236 −2 NA 
13 84 86 32 35 −49 −44 
PtTransfusion Ratea (units PRBC/month)Hemoglobin Valueb (g/L)Reticulocyte Countb (× 109/L)Change in Spleen Volume From Baselinec (%)
Before ESAAfter ESABefore ESAAfter ESABefore ESAAfter ESABefore ESAAfter ESA
2.9 2.9 62 74 42.5 41 −13 −20 
2.2 10.7 75 60 110 114 −22 NA 
1.8 0.7 62 NA 90 NA −29 NA 
0.7 68 66 61 73 −8 −15 
2.9 74 74 167 200 +11 −3 
0.7 2.2 67 73 74 NA −3 NA 
78 88 39 260 −36 −50 
81 80 82 73 −45 −34 
76 80 42 43 −65 −67 
10 74 91 49 76 −54 −58 
11 76 82 106 126 NAd −6 
12 87 84 247 236 −2 NA 
13 84 86 32 35 −49 −44 

NA, no assessment available.

a

Change in PRBC transfusions ± 12 wk of the first administration of ESA.

b

Change in the worst hemoglobin value and the highest reticulocyte count ± 6 wk of the first administration of ESA.

c

% change in spleen volume from baseline to the last assessment prior to and the first assessment after the first administration of ESA.

d

ESA administered before first assessment.

Disclosures:

McMullin:Bristol Myers Squibb: Honoraria; Shire: Honoraria; Novartis: Honoraria. Harrison:Shire: Honoraria, Research Funding; Sanofi: Honoraria; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau. Niederwieser:Novartis: Speakers Bureau. Sirulnik:Novartis: Employment, Equity Ownership. McQuity:Novartis: Employment, Equity Ownership. Stalbovskaya:Novartis: Employment, Equity Ownership. Recher:Janssen Cilag: Membership on an entity's Board of Directors or advisory committees, travel to ASH, travel to ASH Other; sunesis: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Gisslinger:Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; AOP Orphan Pharma AG: Consultancy, Speakers Bureau. Kiladjian:Incyte: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Al- Ali:Sanofi Aventis: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria.

Author notes

*

Asterisk with author names denotes non-ASH members.